Chlorine substituted (1-aryl-2-nitroalkyl) phenols and method of producing same



nited States Patent ()fiice 2,716,667 Fatented Aug. 30, 1955 2,716,667CHLORINE SUBSTITUTED (I-ARYL-Z-NITRO- ALKYL) PHENOLS AND METHOD OF PRO-DUCING SAME Edward B. Hodge, Terre Hautc,

mercial Solvents Corporation, poration of Maryland No Drawing.Application September 25, 1952, Serial No. 311,538

10 Claims. (Cl. 260-619) Y My invention relates to new chlorinesubstituted (1- aryl-Z-nitroalkyDphenols having the formula wherein-R ismethyl or ethyl, Ar is phenyl, p-tolyl, 4- chlorophenyl, or2,4-dich1orophenyl and n is an integer from 1 to 3, the alkali metalsalts of such compounds, and to methods of producing same.

My new compounds are produced by reacting a chlorophenol with asubstituted or unsubstituted 1 -phenyl-2- nitro-l-alkanol. The reactionrequires a catalyst to cause it to proceed. I have found that thisreaction proceeds smoothly and rapidly at easily controlled temperatureswhen catalyzed by concentrated sulfuric acid of a concentration ofgreater than about 70%.

This reaction may be conducted at temperatures ranging from about to 40C., but in the upper part of this range the reaction may become violent.To minimize this effect I prefer to conduct the reaction at from aboutto about C.

The incorporation in the reaction mixture of an organic solvent, whichis inert under the conditions of the reaction, such as cyclohexane,serves to prevent the formation Ind., assignor to Com- Terre Haute,Ind., a corof gummy masses which otherwise hinder the completion of thereaction and complicate the recovery procedure. Therefore, although thereaction will proceed in its absence, I prefer to incorporate arelatively small amount of an inert organic solvent with my reactants.

Chlorophenols which can be reacted in my process include 2-chlorophenol,3-chlorophenol, 4-chlorophenol, 2,5-dichlorophenol, 2,4-dichlorophenol,2,3,6-trichlorophenol, 2,3,5-trichlorophenol, etc. Suitable 1-phenyl-2-nitro-l-alkanols include 1-phenyl-2-nitro-l-propanol, .1-'

phenyl-2-nitro-l-butanol, 1 p chlorophenyl 2-nit'r0-1.- propanol,l-p-chlorophenyl-Z-nitro-l-butanol, 1-p-tolyl-2- nitro-l-propanol, 1 ptolyl-2-nitro-l-butanol, l-(2,4-dichlorophenyl)-2-nitro-l-propanol, 1(2,4-dichlorophenyl)-2-nitro-1-butanol, etc.

Examples of my new compounds which are formed by this reaction include4-(l-p-chlorophenyl-2-nitropropyl)- 2,5-dichlorophenol, 4(1-p-chlorophenyl-Z-nitrobutyl)- 2,5 -dichlorophenol, 4-1-p-tolyl-2-nitrobutyl) -2,5-dichlorophenol, 2 (1 pchlorophenyl-Z-nitrobutyl)-3,4,6-trichlorophenol, 2 (1 pchlorophenyl-Z-nitrobutyl)-4,6- dichlorophenol, 4 (1 pchlorophenyl-2-nitrobutyl)-2- chlorophenol, 2 (1 o,pdichlorophenyl-2-nitrobutyl)- 3,4,6-trichlorophenol, 4-l-o,p-dichlorophenyl-2-nitrobutyl) 2,5 dichlorophenol, 2(1-p-chlorophenyl-Z-nitrobubutyl) -4-chlorophenol, 4-(l-phenyl-Z-nitrobutyl) -2-chlorophenol, and so forth.

The class of chlorine substituted (l-aryl-2-nitroalkyl)- phenols hereinset forth and their alkali metal salts possess properties that make themvery useful in a great variety of ways as antiseptics, bactericides, andpreserving agents. Dilute solutions of these compounds exhibit strongantiseptic action against many species of bacteria, notablyStaphylococcus aureus, Streptococcus faecalis, Streptococcushemolyticus, and Mycobacterium ranae. They are all White, practicallyodorless and tasteless solids with melting points ranging from about 85C to about 240 C. My new chlorine substituted (l-aryl-Z-nitroalkyD-phenols are only slightly soluble in water, but are freely soluble inaqueous solutions of many common organic solvents. They are freelysoluble in organic solvents such as methanol, ethanol, isopropylalcohol, acetone, benzene, chloroform, ethyl acetate and butyl acetate.This solubility in organic solvents makes the compounds useful invarious application forms such as creams, lotions, tinctures, and soforth. They may be dissolved in the above solvents alone or in aqueoussolutions or mixtures of these solvents to form topical solutions.

The alkali metal salts of the products are relatively soluble in water.The potassium salt of4-(l-p-chlorophenyl-2-nitrobutyl)-2,5-dichlorophenol and the sodium saltof 4- 1-p-chlorophenyl-Z-nitropropyl) -2,5-dichlorophenol are bothfreely soluble in Water in concentrations of 5% and 10% of the salts.Solutions of the alkali metal salts show approximately the same level ofactivity as the chlorine substituted (l-aryl-2-nitroalkyl)phenols. Thusthe alkali metal salt forms are very useful in making water solutionsvaluable as non-irritant skin disinfectants, mouth washes, etc.

The following examples are offered to illustrate my invention and it isto be understood that I do not intend to be limited to the exact amountsand procedures set forth therein. The scope of the invention is asdefined in this specification and the attached claims and I intend forall equivalents thereof apparent to those skilled in the art to bespecifically included within said scope. Concentrations of the sulfuricacid and inert organic solvents may be varied greatly and the reactiontime and reaction temperature may be changed.

EXAMPLE I To 200 grams of 92% sulfuric acid plus 10 ml. of cyclohexanecooled in a water bath was added slowly a solution of 29.5 gm. (0.18mol) of 2,5-dichlorophenol in 38 gm. ofl-p-chlorophenyl-2-nitro-l-butanol plus 7 ml. of cyclohexane. Themixture was stirred during addition, and the temperature was held at 17to 19 C. Stirring was continued for 10 minutes after the addition wascompleted. (Total reaction time, 70 minutes.) Twenty-five ml. more ofcyclohexane were added and then the mixture was poured into 400 ml. ofwater. This was then filtered and the precipitate was washed withseveral 10 ml. portions of cyclohexane to give 40 gm. (65% yield) ofalmost-white product. A sample for analysis was recrystallized frombenzene. The recrystallized 4 (1 pchlorophenyl-Z-nitrobutyl)-2,5-dichlorophenol had a melting point of189-1895 C. Theoretical analysis for the compound is 28.39% chlorine and3.74% nitrogen. The analysis showed 28.10% chlorine and 3.54% nitrogen.

EXAMPLE II To a stirred mixture of 55.5 grams of 2,5-dichlorophenol and123.6 grams of sulfuric acid cooled in an ice water bath to 20 C. wasadded dropwise 66.7 grams of 2-nitro-l-p-chlorophenyl-l-propanol. Themixture was stirred for 20 minutes longer and left standing toprecipitate. The mixture was filtered through sintered glass and theprecipitate washed with ml. of cyclohexane to give 80.8 grams of4-(l-p-chlorophenyl- Z-nitropropyl)-2,5-dichlorophenol representing ayield of 65%. Recrystallization from a benzene-cyclohexane mixture gavea sample of melting point 178l80 C. analyzing 29.50% chlorine and 3.72%nitrogen against theoretical values of 29.59% chlorine and 3.88%nitrogen.

EXAMPLE III To a mixture of ml. of 93% sulfuric acid and l 0 ml. ofcyclohexane at 1820 C. was added over 45 minutes a solution of 32.6grams of 2,4-dichlorophenl in 50 grams of crudeZ-nitro-l-p-chlorophenyl-l-butanol and ml. of cyclohexane. The reactionwas cooled by tap water and stirred for 4 hours after addition of thedichlorophenol solution. The reaction mixture was poured into 500 ml. ofwater, stirred, and the water decanted. To the organic layer remainingwas added 100 ml. of concentrated sulfuric acid with stirring for 30minutes. The mixture was again poured into 500 ml. of water and stirredwhile cooling. Filtration yielded 34- grams of crude 2 (lp-chlorophenyl-Z-nitrobutyl)-4,6-dichlorophenol. Recrystallization of asample from a benzenecyclohexane mixture gave a white powder of meltingpoint l30.5l32 C. and analysis of 28.41% chlorine and Now havingdescribed my invention, what I claim is:

1. As a new composition of matter, a compound selected from the groupconsisting of the compounds represented by the formulaHOCsHnCl4-1tCH(Ar) CH(NO2) R wherein R is selected from the groupconsisting of methyl and ethyl, Ar is selected from the group consistingof phenyl, p-tolyl, 4-chlorophenyl, and 2,4-dichlorophenyl, and n is aninteger from 1 to 3, and alkali metal salts thereof.

2. The compound 4-(1-p-chlorophenyl-2-nitropropyl)- 2,5-dichlorophenol.

3. The potassium salt of 4-(l-p-chlorophenyl-Z-nitro- 3.62% nitrogenagainst a theoretical analysis of 28.39% y P chlorine and 3 74% nitrogen4. The compound 4-(1-p-tolyl-2-nitrobuty1)2,S-dichlo- To illustrate thepreparation of the alkali metal salts p of these new compounds thefollowing example is in- The F p 1} P Y cluded. butyl) -2,5-d1ch1oropheno1.

EXAMPLE IV 6. The sodium salt of4-(1-p-chloi:ophenyl-2-nitropropyl)-2,5-dichloi:ophenol. To a Solunon.of (.0001 mol) of 7. A process for the production of compoundsreprechlorophenyl-2-nitropropyl)-2,5-dichlorophenol from Exsented by theformula ample II in 2.5 ml. of ethanol was added a solution of 0.5 gm.0.0011 mol) of sodium methoxide in 2.5 ml. of M- )C (N 2)R ethanol. Thismixture was then added to l-OO ml. of wherein R15 selected {mm the groupconsisting of methyl petroleum ether. A crystalline precipitate weighing0.25 and ethyl, is Selected from the group consisting of gm. formed.This analyzed 3.66 nitrogen. Theory phenyl, pjtolyl, 4 chlol.ophenyl,and 2,4 dich10mpheny1, tor the monosodium salt 18 3.36%, for thedisodium salt and n is an integer from 1 to 3, which comprises reacting1s a compound represented by the formula All of the compounds set out inthe group show antiseptic action against several species of bacteria,but they HOCGHflClE-fl exhibit a wide range of activity toward thesemicroorganh i n i an integer fro 2 to 4 with a compound isms. Ingeneral, for compounds of similar structure, presented b h f r ul thepresence of the hydroxyl group in the para position gives a higherantibacterial activity than when that group 0 HOCH(AI)CH(NO2)R is in theortho position. These compounds are more wherein R is selected from thegroup consisting of methyl active toward gram-positive and Mycobacteriathan toand ethyl and Ar is selected from the group consisting wardgram-negative bacteria. The antibacterial activity of phenyl, p-tolyl,4-ch1orophenyl, and 2,4-dichlorophenyl of several examples of these newcompounds and their 40 in the presence of sulfuric acid of aconcentration of alkali metal salts is set out in Table I below whichshows greater than about 70 per cent and recovering the prodthe minimuminhibitory concentration in micrograms uct formed. per milliliter of thecompounds tested against the various 8. The process as set forth inclaim 7 wherein the strains of bacteria. The compounds tested were:reaction is carried out in the presence of an inert organic Ke to Table1 y 9. The process as set out in claim 7 above wherein the reaction iscarried out at a temperature of from 0 to Number Compound 350 C.

10. The process as set out in claim 7 above wherein itltgIgtififfigififitiitfiitigtfitgg?fiigfiiggt ifit the rqacfioln iscarried t n he pres nce of an inert .4-l-- -2-'t t-,- r o 2-(l-g-c iliirop lieifyl 2hitrobutgfi)- t ?6-%i i?zhlorophen0l. do orgamc so ventat a temperature of from 0 to 35 C' 2-0 p-chlorophenyl-2-nitrobutyl)-4,6-dichlorophenol.

-eiii o pen izni ob i yl)grei io he oi 111 References Cited in the fileof this patent --o,-i o I1--Il1l01l'-,, ricoi-o- 4 iihent lh m b t mm h1 UNITED STATES PATENTS 8 -lC 0Y0 eny- DIIOUY', '10 0Y0 8H0. 9 sdifill'nc n 1 -(l-p-chlorophenyl-Z-nitropropylfiZ, frdi- 1,880,566 weileret a1Oct. 4, 1932 8110 10 P ta s iii in salt of 4(l-p-chloropheny1-2-nittobutyl)-2, 5-

diehlorophenol.

Table I INHIBITORY CONCENTRATIONS 0F COMPOUNDS EXAMINED MinimumInhibitory Concentrations (Micro. g./m1.) against- St it. St St 6 r P t.Shz Myco. Myco. au i us fec rfl i s hein o E 6021 pseifsoth. dysent riaeSpp.607 ranae 1 Partial inhibition.

1. AS A NEW COMPOSITION OF MATTER, A COMPOUND SELECTED FROM THE GROUPCONSISTING OF THE COMPOUNDS REPRESENTED BY THE FORMULA